Roles of hypoxia inducible factors in viral infection: Are they a potential therapeutic target?

Abstract

As a crucial nuclear transcription factor, hypoxia-inducible factor (HIF) serves essential functions in mediating cellular responses to hypoxic stress. Through oxygen-sensing mechanisms, HIF initiates downstream signaling cascades that coordinate metabolic reprogramming, immune modulation, and oncogenic progression in oxygen-deficient microenvironments. Current evidence positions HIF at the convergence of various pathologies, including microbial pathogenesis, carcinogenesis, and inflammatory disorders. This systematic review summarizes recent advances in HIF-mediated immunomodulation and virological mechanisms. The analysis emphasizes the fundamental importance of investigating HIF-related molecular pathways to address significant gaps in basic research.

Keywords: Hypoxia inducible factor; hypoxia; immunization; normoxia; virus infection.

Figure 1.

Role of HIF in viral infection. The complexity of the virus-host relationship reflects the different roles played by HIF in different viral infections. HPV—human papilloma virus, HBV—hepatitis B virus, HCV—hepatitis C virus, EBV—Epstein-Barr virus, kaposi’s sarcoma-associated herpesvirus – KSHV, RSV—respiratory syncytial virus, IAV—influenza a virus, SARS-CoV-2—Severe acute respiratory syndrome coronavirus 2, HIF-1α—hypoxia inducible factor 1α, HIF-1β—hypoxia inducible factor 1β, latency associated nuclear antigen – LANA, vGPCR – viral G-protein coupled receptor, LMP-1—Latent membrane protein-1, vIRF3—viral IFN regulatory factor 3, NO—nitrogen monoxide, MTA1—metastasis associated protein 1, HDACs – histone deacetylases, AP-1—Activation protein 1, EBNA1—Epstein - barr virus nuclear antigen, HRE – hypoxia-responsive element, PHD – prolyl hydroxylase domain, ROS – reactive oxygen species, mito-ROS – mitochondrial ROS, siah-1—E3 ubiquitin-protein ligase siah-1, ORF—Open reading frame, FIH – factor inhibiting HIF, CBP – cAMP-response element binding protein, p-VHL – tumor suppressor protein von hippel-lindau, PTEN – phosphatase and tensin homolog deleted on chromosome ten, TXNIP—thioredoxin interacting protein.